{"paper_id":"6fbe3fd8-fd4f-4aca-8320-69141449c0de","body_text":"Endometriosis is a chronic disease characterized by the presence of endometrial\ntissue (glands and stroma) outside the uterine cavity. It is estimated to affect\naround 10% of women of reproductive age and is even more common in infertile\npatients ( Supermaniam & Thye, 2021 ).\nEndometriomas are the ovarian manifestation of the disease and are found in 17-44% of\npatients ( Alborzi  et al. ,\n2019 ). They are diagnosed by ultrasound scanning and are usually\nassociated with advanced stages of endometriosis ( Alborzi  et al. , 2019 ). It is believed that\nendometriomas can affect ovarian physiology by mechanical stretching and local\ninflammation, promoting oxidative stress in the surrounding ovarian cortex that\ncould lead to apoptosis and necrosis of early follicles ( Leone Roberti Maggiore  et al. , 2017 ).\nInfertility is one of the challenges that women with endometriosis face and surgery\nis believed to increase pregnancy rates over no treatment or diagnostic laparoscopy\n( Bafort  et al. , 2020 ;\n Hodgson  et al. , 2020 ;\n Becker  et al. , 2022 ).\nHowever, we believe that the surgical treatment for endometriomas, while improving\nthe changes of natural pregnancy can, paradoxically, impair the outcomes of assisted\nreproductive treatment, if needed in the future.\nEndometriomas may have a negative impact on pregnancy rates and some studies have\ninvestigated whether their surgical removal is associated with higher changes of\nspontaneous pregnancy ( Alborzi  et\nal. , 2019 ;  Leone Roberti\nMaggiore  et al. , 2017 ;  Maul  et al. , 2014 ). There are no studies\ncomparing the surgical removal of endometriomas with expectant management for\nthis outcome.\nRetrospective data on 550 women with ovarian endometriotic cysts who underwent\ncystectomy was analyzed. The follow up cohort was composed of 289 patients, of\nwhom 111 women reported pregnancy desire. The postoperative spontaneous\npregnancy rate was 54.1% ( Maul  et\nal. , 2014 ).\nA cohort of 100 women who had surgery for endometrioma removal was followed for\n12 months before being referred to assisted reproductive treatment (ART) if a\nspontaneous pregnancy was not achieved. Cystectomy was performed in 52 patients\nand fenestration and coagulation in 48 patients. The spontaneous pregnancy rate\nof infertile women was 59.4% in the cystectomy group and 23.3% in the\nfenestration group after one year of follow-up ( Alborzi  et al. , 2004 ). The same author performed a\nsystematic review and meta-analysis of different endometrioma treatments for\ninfertility, including surgery and assisted reproductive treatment. Although\nthere were no statistically significant differences in clinical pregnancy rate\nbetween groups, the surgery-alone group had the highest pregnancy rate (43.8%)\nwhen compared to the other groups (surgery + ART, ART alone and sclerotherapy +\nART) ( Alborzi  et al. ,\n2019 ).\nA case series of 143 women who underwent endometrioma cystectomy for chronic\npelvic pain and/or infertility evaluated pregnancy rate in the seventy-six\npatients who wished to become pregnant. The mean age of patients was 31.9 years.\nAfter surgery, 42.1% of women conceived spontaneously at a mean duration of 6.9\nmonths and 6.6% of patients conceived twice after surgery ( Supermaniam & Thye, 2021 ).\nA study highlighted that ‘no RCT or meta-analysis are available to answer the\nquestion whether surgical excision of moderate to severe endometriosis enhances\npregnancy rates’ ( Vercellini  et\nal. , 2009 ). The authors evaluated uncontrolled studies\nreporting the impact of laparoscopic treatment of endometriomas on reproductive\noutcomes. They found that the pregnancy rate varies from 30% to 67% in the\nstudies, with an overall weighted mean of 50%. They acknowledge, however, the\npotential for selection and publication bias ( Vercellini  et al. , 2009 ). Another review on\nendometrioma treatment for fertility improvement found that cumulative pregnancy\nrates after surgery varied between 22.3% and 48.9%, with the highest rates being\nachieved after cystectomy technique ( Leone\nRoberti Maggiore  et al. , 2017 ).\nThe European Society for Human Reproduction and Embriology (ESHRE) acknowledges\nthat data from comparative studies are lacking but clinicians may consider\nlaparoscopic treatment of endometrioma in infertile patients for improving\nnatural pregnancy chances ( Becker  et\nal. , 2022 ). As regarding the surgical technique, results\nseem to be best with cystectomy when compared to fenestration/coagulation and\nlaser vaporization ( Becker  et\nal. , 2022 ).\n\nEndometriosis surgery can relieve pain symptoms, restore pelvic anatomy, and improve\nfertility outcomes ( Zakhari  et al. ,\n2021 ;  Koga  et al. ,\n2015 ). Eradication of endometriotic lesions during surgery diminishes the\nchance of disease recurrence ( Chiu  et\nal. , 2022 ). However, reoperation rates are estimated to be\nbetween 27% and 58% when the ovaries are preserved ( Zakhari  et al. , 2021 ). Endometriomas could relapse due\nto regrowth of residual lesions, ovulation and retrograde menstruation leading to\n de novo  lesions ( Koga\n et al. , 2015 ;  Chiu\n et al. , 2022 ). Most of recurrence cases involve the\npreviously treated ovary ( Koga  et\nal. , 2015 ).\nSurgery can remove all, or at least most, of the ectopic endometrial tissue.\nTherefore, post-operative hormonal suppression is a strategy that minimizes\novulation, endometrial cells activity and their risk of reimplanting in the\nperitoneal cavity ( Zakhari  et al. ,\n2021 ).\nA systematic review and metanalysis evaluated women who underwent cystectomy for\nendometrioma followed by hormonal suppression or expectant management for at least\n12 months. The authors found that hormonal treatment decreased endometrioma\nrecurrence, with the best results for dienogest associated with gonadotropin\nreleasing hormone agonist (GnRHa), followed by dienogest alone and oral combined\ncontraceptive pill associated with GnRHa ( Chiu\n et al. , 2022 ).\nKoga et al. concluded that prevention of pain symptoms recurrence was only achieved\nwith long-term oral contraceptive use (more than 6 months). Regarding endometrioma\nrecurrence, oral contraceptive use for 2 years or more demonstrated significantly\nprotective effect. Moreover, recurrence was frequently observed in patients who\ndiscontinued treatment. Regarding the administration regimen, the studies analyzed\nfound no difference between cyclic or continuous regimens ( Koga  et al. , 2015 ).\nA retrospective study reviewed data on 206 women surgically treated for moderate or\nsevere endometriosis between 2004 and 2014. The stage of disease was not associated\nwith recurrence risk. Interestingly, the recurrence rate was lower in patients who\ndid not receive pharmacological treatment after surgery. The authors attribute this\ndifference to the fact that most of these patients became pregnant after the\nprocedure, which may have reduced the recurrence rate during the study time ( Schippert  et al. , 2020 ).\nA systematic review and metanalysis concluded that patients receiving post-operative\nhormonal suppression therapy were significantly less likely to experience disease\nrecurrence and had significantly lower pain scores when compared to controls ( Zakhari  et al. , 2021 ). On the\nother hand, a randomized controlled trial showed no difference in endometrioma\nrecurrence after a year of LNG-IUS use compared to expectant management in patients\nundergoing laparoscopic cystectomy followed by 6 months of GnRHa ( Chen  et al. , 2017 ). This may\nsuggest that ovulatory suppression after surgery is important to prevent ovarian\ndisease recurrence.\nRegarding surgical techniques, a Cochrane Systematic Review and Metanalysis concluded\nthat excision of the cyst wall in endometriomas larger than 3 cm in size was\nassociated with reduced recurrence rate of dysmenorrhea, dyspareunia, acyclic pelvic\npain, and reduced recurrence of the endometrioma itself ( Hart  et al. , 2008 ).\nBased on the above results and other several studies, ESHRE stated in the latest\nendometriosis guideline that “After surgical management of ovarian endometrioma in\nwomen not immediately seeking conception, clinicians are recommended to offer\nlong-term hormone treatment for the secondary prevention of endometrioma and\nendometriosis-associated related symptom recurrence”. Regarding the type of\nprocedure, cystectomy is probably superior to drainage and coagulation ( Becker  et al. , 2022 ).\nWomen who wish to become pregnant and have endometriomas could benefit from surgery\nto enhance cumulative pregnancy rates. Paradoxically, the best approach to prevent\ndisease relapse cannot be offered to these patients. Therefore, while trying to\nconceive these women are subject to a greater risk of endometrioma recurrence.\n\nThe choice to whether pursue a spontaneous pregnancy or directly initiate an assisted\nreproductive treatment after endometriosis surgery is a matter of debate. The\nendometriosis fertility index (EFI) is a staging system first published in 2010 to\nestimate the natural conception rate after laparoscopic surgery for endometriosis\n( Vesali  et al. , 2020 ).\nIt should be used for postoperative counselling to decide between assisted\nreproductive treatment and nonART management ( Tomassetti, 2020 ).\nThe EFI considers historical factors, such as age, duration of infertility, and\npregnancy history together with surgical factors. The latter are based on the AFS\nscore and the so called ‘least function score’, determined by the surgeon at the end\nof the procedure for each of the tube, fimbria, and ovary. The sum of both\nhistorical and surgical factors results in the EFI score ( Adamson & Pasta, 2010 ). The score ranges from 0 to 10 and\nestimates the natural pregnancy rate within 3 years after surgery. It has been\nexternally validated since its first publication in 2010.\nA systematic review and metanalysis of 17 studies that included over 3000 women found\nthat the cumulative nonART pregnancy rate at 36 months was 10% for the lowest EFI\nscore and 69% for the highest. The area under the curve (AUC) of the score for\npregnancy prediction varied between 64% and 85%. The authors acknowledge, however,\nthe high heterogeneity between studies ( Vesali\n et al. , 2020 ). A retrospective cohort study of 235\npatients with stage III/IV endometriosis who underwent fertility-sparing surgery\nshowed that sixty-three percent of patients had a live birth following treatment,\n64% of them without ART. The mean follow-up period was 4.1 years. The authors\nobserved that women with an EFI score of 0-2 had no live births within 5 years of\nfollow-up and this number steadily increased up to 91% with an EFI score of 9-10\n( Maheux-Lacroix  et al. ,\n2017 ).\nThe revised American Society for Reproductive Medicine (rASRM) score classifies\nendometriosis in minimal, mild, moderate, and severe disease (stages I, II, III and\nIV) ( ASRM, 1997 ). According to this\nclassification, ovarian endometrioma is already a marker of moderate disease. The\npresence of an endometrioma reduces the AFS score of the EFI to 0 and reduces the\nleast function score ( Adamson & Pasta,\n2010 ). Therefore, even if the only endometriosis manifestation in the\npatient is a single endometrioma, and all the historical factors are of good\nprognosis, this patient will have an EFI of 8, which gives a cumulative pregnancy\nrate of 40% within one year after surgery ( Adamson\n& Pasta, 2010 ).\nAccording to the exposed above, at least 60% of patients with endometrioma will need\nassisted reproductive treatment after its removal. Surgery can also reduce ovarian\nreserve, as already demonstrated by the reduction of antimüllerian hormone\nlevels (AMH) and antral follicle count (AFC) ( Leone\nRoberti Maggiore  et al. , 2017 ;  Somigliana  et al. , 2012 ). Cystectomy, despite\nbeing the best approach to increase spontaneous pregnancy rates and decrease\nrecurrence rates, has a greater negative impact on AMH and AFC ( Daniilidis  et al. , 2023 ;  Adamyan  et al. , 2023 ). The\ndamage to ovarian reserve is more pronounced in patients with bilateral\nendometriomas and cysts with a mean diameter >5cm ( Daniilidis  et al. , 2023 ). Therefore, it is\nreasonable to consider how much endometriomas could impact ovarian response to\nstimulation and if ovarian surgery would have an even more deleterious effect on IVF\noutcomes.\nA study showed a reduced impact on ovarian reserve with less invasive methods, such\nas sclerotherapy, when compared to cystectomy. The sample size, however, was small\n( Vaduva  et al. , 2023 ). A\nnarrative review reported similar AMH decrement at 6 months postoperatively after\nsclerotherapy and cystectomy in two studies, but a significant negative impact on\novarian reserve after cystectomy in another study ( Jee, 2022 ). Regarding pregnancy rates after IVF, data is still\ncontroversial, with some studies showing that the sclerotherapy group had better\nrates than the cystectomy group, while others show similar results. When analyzing\nspontaneous pregnancy rates after both treatments, the results are the same. It is\nalso important to consider that, although a less invasive approach, sclerotherapy\ncan have complications such as abdominal pain, ovarian abscess and intraperitoneal\nhemorrhage ( Jee, 2022 ). Nevertheless, the\nprocedure could be considered as an alternative management for endometriomas to\nminimize ovarian tissue damage in some cases.\nThe question of whether endometriomas affect ovarian response to controlled\nstimulation is limited by the fact that, in most cases, endometriomas are unilateral\nand therefore the contralateral ovary could compensate for the reduced function.\nMoreover, studies do not usually distinguish between patients who underwent\nendometrioma surgery before IVF and those who did not had surgery ( Somigliana  et al. , 2006 ). A\nsystematic review and metanalysis of 17 studies reported fewer number of oocytes,\nmature oocytes and total embryos formed in patients with endometriomas compared to\nthose without. When comparing only cases with unilateral endometriomas, the affected\novary had fewer co-dominant follicles than the intact one ( Yang  et al. , 2015 ).\nA reduced responsiveness to gonadotropins in the presence of ovarian endometriomas\nwas reported, which was more evident in women with larger cysts ( Somigliana  et al. , 2006 ).\nGonzález-Foruria et al. retrospectively analyzed data on infertile patients\nwith at least one ovarian endometrioma undergoing their first IVF/ICSI cycle\ncompared with control women without endometriosis. They found endometrioma patients\nrequired significantly higher gonadotropin dose for stimulation and had a\nsignificantly lower number of follicles >14mm, oocytes retrieved and mature\noocytes ( González-Foruria  et\nal. , 2020 ). Another study reported that the ovarian response\nto stimulation in terms of number of oocytes retrieved was poorer in endometrioma\npatients compared to tubal factor controls and decreased significantly in subsequent\ncycles ( Al-Azemi  et al. ,\n2000 ).\nA multicenter retrospective cohort study tried to eliminate the bias of having a\nnormal ovary compensating a contralateral endometrioma. The authors analyzed 39\nwomen with unoperated bilateral endometriomas matched with 78 unexposed controls\nundergoing ovarian stimulation for IVF/ICSI and found fewer number of developing\nfollicles and oocytes retrieved in the endometrioma patients’ group. The total dose\nof gonadotropins used and number of days of stimulation did not differ between cases\nand controls ( Benaglia  et al. ,\n2013 ).\nSeveral studies suggest a reduced response to ovarian stimulation in women with\nendometriomas. It is also a matter of debate whether endometrioma surgery would\nimpair or improve ovarian response and in vitro fertilization outcomes. Demirdag\n et al.  compared the IVF outcomes of women previously operated\nfor endometriomas with women who did not undergo surgery and a control group with no\nendometriosis. Their results showed that women with previous endometrioma surgery\nhad fewer number of oocytes retrieved and mature oocytes, a higher cycle\ncancellation rate and a higher incidence of poor response to stimulation compared to\nthe other groups. The clinical pregnancy rates and live birth rates, however, were\nsimilar between groups ( Demirdag  et\nal. , 2021 ).\nA meta-analysis of 21 studies analyzed the pros and cons of stripping ovarian\nendometriomas before IVF/ICSI. The analysis showed that the total amount of\ngonadotropins used was higher in women who underwent endometrioma cystectomy, but\nthe duration of stimulation was similar between groups. The number of dominant\nfollicles and number of oocytes retrieved was lower in patients with previous\nsurgery when compared to conservative approach. Despite the lower number of oocytes\navailable, the total formed embryos, pregnancy and live birth rates were similar in\nthe pooled analysis. The heterogeneity between studies was considered low ( Tao  et al. , 2017 ).\nEndometrioma surgery is known to pose a threat to ovarian reserve ( Tao  et al. , 2017 ). Women with\ndiminished ovarian reserve (DOR) may also have a poor response to ovarian\nstimulation ( Conforti  et al. ,\n2019 ). A retrospective case-control study tried to determine whether\nthere were differences on IVF/ICSI outcomes between women with DOR following\nendometrioma surgical approach when compared to DOR without ovarian surgery. The\nauthors found no differences between groups regarding number of oocytes retrieved\nand mature oocytes, cycle cancelation rates, total dose of gonadotropins\nadministered and live birth rates ( Hong  et\nal. , 2017 ). These results indicate that the poorer outcomes\nof endometrioma surgery may be related to the impact on ovarian reserve rather than\nthe disease itself.\nMost studies that demonstrated a negative impact of endometrioma surgery on ovarian\nresponse to stimulation also showed no differences regarding pregnancy and live\nbirth rates between groups ( Al-Azemi  et\nal. , 2000 ;  Benaglia\n et al. , 2013 ;  Demirdag  et al. , 2021 ;  Tao  et al. , 2017 ). The obstetrical outcome in most\nstudies is clinical pregnancy and live birth rate per embryo transfer ( González-Foruria  et al .,\n2020 ,  Tao  et al .,\n2017 ,  Conforti  et al .,\n2019 ) and not cumulative pregnancy rate per started cycle. Patients with\nprevious endometrioma surgery have systematically a lower number of oocytes and\nembryos and, therefore, are expected to have a lower cumulative pregnancy rate and\nlower chances of a future pregnancy. Another point to consider is that the mean age\nof patients in those studies was less than 35 years old and in most of them,\nfertility duration was between 2 and 3 years ( Al-Azemi  et al. , 2000 ;  Benaglia  et al. , 2013 ;  Tao  et al. , 2017 ;  Zeng\n et al. , 2022 ). Therefore, patients were considered\nof good prognosis. It is reasonable to consider that older women might have a\ngreater deleterious impact of surgery on ovarian reserve and assisted reproductive\noutcomes. Indeed, Geber et al. stratified patients by age (<=35 years and\n>35years) and found that older patients with previous endometrioma surgery not\nonly had less follicles and oocytes retrieved but also a lower pregnancy rate (34.5%\n vs . 48.3%). Although the latest outcome failed to reach\nstatistical significance, their sample size was small (29 patients in each group)\n( Geber  et al. ,\n2002 ).\nSince maternal age is the most important factor determining the likelihood of\nconception in assisted reproductive treatments ( Irani  et al. , 2019 ), it is possible that in older\npatients the ART treatment outcomes after endometrioma surgery may be more severely\naffected. Also, in younger patients the aneuploidy rates are lower and, therefore,\nfew oocytes are needed to obtain an euploid blastocyst ( Haahr  et al. , 2018 ). Considering that women\nare delaying childbirth, more patients will need assisted reproductive treatments in\nthe future ( Guzman  et al. ,\n2019 ). For the ones affected by endometriosis, it is likely that ovarian\nsurgery could be harmful for their reproductive future. Despite being the best\napproach for enhancing the chances of natural pregnancy, endometrioma cystectomy can\nparadoxically reduce the future pregnancy and cumulative live birth rates if IVF is\nneeded, considering that older patients systematically have fewer oocytes and more\naneuploid embryos.\n\nTo enhance the spontaneous pregnancy rates in women with endometrioma, the surgical\nremoval of cysts can be indicated in some cases. The gold standard technique is\ncystectomy and hormonal suppression is indicated to reduce recurrence rates.\nHowever, patients trying to conceive cannot be offered this approach and are subject\nto a greater disease recurrence rate. Moreover, endometrioma surgery can reduce\novarian reserve, which can be deleterious for assisted reproductive treatment,\nespecially in women of advanced age. The paradox of the management of endometriomas\nin infertile patients is that approximately 60% of women with endometriomas will\nneed ART in the future and, therefore, the procedure that can be offered to enhance\nspontaneous pregnancy rates in these patients can also worsen their future assisted\nreproductive outcomes.","source_license":"public-domain-us","license_restricted":false}